Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/30—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

• the present invention relates to novel derivatives of nitrogen-containing heterocyclic methanols, encompassing derivatives of pyrrolidine, piperidine, homopiperidine and pyridine methanols, having ⁇ -aryloxymethyl substitution and certain double ethers thereof.
• the compounds are use­ful in treating cardiac related conditions in animals.
• novel aryloxymethyl derivatives of heterocyclic methanols of this invention have the formula: wherein Z represents R1 represents a hydrogen atom, loweralkyl or carbethoxymethyl group; R2 represents a hydrogen atom, loweralkyl or cycloalkyl, phenyl, phenyl substituted with from 1 to 3 radicals which may be the same or different, the radicals being a halogen atom, or a loweralkyl, loweralkoxy, nitro or trifluoromethyl group, or phenyl-loweralkyl group; R3 represents an aryl group which is 1 or 2-naphthalenyl, 2,3-­dihydroinden-4-yl,2,3-dihydroinden-5-yl, phenyl or phenyl substituted by one to three radicals where each radical individually represents a loweralkyl loweralkoxy halogen trifluoromethyl, phenyl, methylenedioxy, nitro, amino, loweralkylamin
• loweralkyl as used herein, unless otherwise specified, includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, amyl, isoamyl, hexyl, heptyl and octyl radicals and the like.
• loweralkoxy has the formula -O-loweralkyl.
• cycloalkyl as used herein includes primarily cyclic alkyl radicals containing 3-9 carbon atoms inclusive and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and the like.
• halo or halogen when referred to herein include fluorine, chlorine, bromine and iodine unless otherwise stated.
• Phenyl in the definition of R2 may include from 1 to 3 common non-interfering radicals exemplified by halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl and the like.
• double ether is meant a compound having an "-O-loweralkyl” group in addition to the aryloxy group represented by "-OR3" in Formula I.
• “Pharmaceutically acceptable salts” include acid addition salts and hydrates of the compounds of Formula I which are physiologically compatible in warm blooded animals.
• the acid addition salts may be formed by either strong or weak acids.
• strong acids are hydrochloric, sulfuric and phosphoric acids.
• weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, hexamic and the like.
• loweracylamino is meant loweralkyl- -NH-.
• the compounds of the present invention act to correct ouabain-induced cardiac arrhythmias and/or lower blood pressure in hypertensive living animals as described more fully hereinbelow under "Pharmacology.”
• the use of the compounds in treating cardiac arrhythmias and hyper­tension in living animals comprises administering compounds of Formula I to a living animal body for cardiac arrhythmic effect and/or blood pressure-lowering effect in an effective amount to control arrhythmia and/or blood pressure as set forth hereinbelow under "Pharmaceutical Compositions and Administration.”
• Preferred compounds of Formula I have any or all of the following characteristics a) to f):
• R1 loweralkyl
• R1 loweralkyl
• R1 loweralkyl
• Certain compounds of Formula I may be alkylated on pyrrolidine, piperidine or homopiperidine nitrogen by using a 1:1 molar ratio of loweralkyl iodide under mildly basic conditions illustrated by the following equation:
• Certain compounds of Formula I may be alkylated on pyrrolidine, piperidine or homopiperidine nitrogen and on the hydroxy group as well by using a strong base; e.g., sodium hydride, along with 2 moles of loweralkyl halide; e.g., bromide, as illustrated by the following equation:
• Compounds of Formula I wherein R3 is aminophenyl may be prepared by reducing the corresponding nitro compound with iron powder and hydrochloric acid at about 25-80°C.
• Compounds of Formula I wherein R3 is monomethylamino­phenyl and Z is other than pyridino may also be prepared by reacting the corresponding 1-benzylaminophenyl compound with methyl chloroformate and reducing the urethane obtained with lithium aluminum hydride followed by debenzylating with palladium on carbon with hydrogen.
• Compounds of Formula I wherein R3 is dimethylamino­phenyl may also be prepared by reacting the corresponding aminophenyl compound with more than 2 equivalents of formaldehyde and cyanoborohydride in a solvent such as acetonitrile under mildy acidic conditions as provided by the use of glacial acetic acid.
• Compounds of Formula I wherein Z is pyridino and R3 is monomethylaminophenyl may also be prepared by controlling the formaldehyde to 1 to 1.3 equivalents per mole of the amino-phenyl compound with cyanoborohydride in mildly acidic acetonitrile.
• a preferred process for preparing pyridinyl and piperidinyl compounds of Formula I is comprised of the following steps: optionally step 1, brominating a pyridine compound having the formula: to give a compound having the formula: optionally Step 2, reacting a compound preparable in Step 1 with a reducing agent, e.g. sodium borohydride in an aprotic solvent; e.g. methanol, to give a compound having the formula:
• a reducing agent e.g. sodium borohydride in an aprotic solvent
• aprotic solvent e.g. methanol
• Step 3 reacting a compound preparable in Step 2 with a compound having the formula: Na ⁇ O ⁇ R3 wherein R3 is an aryl group selected from 1 and 2-naphthalenyl, 2,3-dihydroinden-4 or 5 yl, phenyl, or phenyl substituted by loweralkyl, loweralkoxy, halogen, trifluoromethyl, phenyl, methylenedioxy, nitro, monomethylamino, dimethylamino, or loweracylamino to give a compound having the formula: wherein R3 is as defined above; optionally Step 4, reacting a compound preparable in Step 3 with sodium hydride in a suitable solvent; e.g., tetrahydrofuran, and a reagant having the formula: R1X wherein R1 represents a loweralkyl or carbethoxymethyl group and X represents chlorine, bromine, or iodine to give a compound having the formula: wherein R3 is as defined
• a crystalline oxalate salt was obtained by using equimolar quantities of the free base and oxalic acid.
• the oxalate salt was recrystal­lized twice from methanol-ethyl acetate to give 6.10 g (33.6%) of white crystalline product, m.p. 129-132°C.
• a solution of sodium phenoxide was prepared by slowly adding, with stirring and under nitrogen, a solution of phenol (37.6 g, 0.4 mole) in 300 ml of tetrahydrofuran (THF) (distilled from lithium aluminum hydride) to a mixture of sodium hydride (50% dispersion in oil, 19.2 g, 0.4 mole washed with petroleum ether) in 500 ml of THF. This addition was made over a 3 hr period. After stirring for an additional 15 minutes, evolution of hydrogen ceased. 1-(2 ⁇ -Pyridyl)-2-bromoethanol* hydrobromide (28.1 g, 0.1 mole) was added in solid portions over a period of 30 min. The solution was refluxed overnight.
• THF tetrahydrofuran
• This bromohydrin was prepared from 2-acetylpyridine by bromination followed by sodium borohydride reduction of the brominated acetylpyridine.
• the bromohydrin was isolated as the hydrobromide salt. See L. Polo Friz, Farmco Ed. Sci. 18 (12, 972-980, 1963.
• a solution of sodium naphthoxide was prepared by adding slowly with stirring and under nitrogen a solution of ⁇ -naphthol (50.62 g, 0.35 mol) in 300 ml of tetrahydro­furan (THF) to a suspension of 16.87 g of 50% sodium hydride (8.44 g, 0.35 mole) in 500 ml of THF. This addition was made over a 2 hr period. After stirring for an additional 15 minutes, evolution of hydrogen ceased.
• 1-(2 ⁇ -Pyridyl)-2-bromoethanol* hydrobromide (24.5 g, 0.0878 mole) was added in solid portions over a 30 minute period, and the reaction mixture was refluxed overnight.
• the tetrahydrofuran was removed on the rotary evaporator, and the brown residue was dissolved in 600 ml of water.
• the aqueous phase was extracted with diethyl ether, and the ether layer was back-extracted with 10% sodium hydroxide.
• the ether layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporator to give a brown oil.
• the oil was recrystallized from acetone-petroleum ether to give solid free base, m.p. 107-108.5°C.
• the free base was dissolved in methylene chloride and converted to the hydrochloride salt by addition of ethereal hydrogen chloride with additional diethyl ether.
• a solution of the soidum salt of 4-indanol in tetra­hydrofuran was prepared by the addition of a solution of 4-indanol (100.0 g, 0.747 mole) in 400 ml of tetrahydrofuran to sodium hydride (33.9 g, 0.747 mole) which was previously washed with hexane, dried under nitrogen atmosphere and suspended in 650 ml of tetrahydrofuran. The resulting solution was stirred an additional 0.5 hr (under nitrogen atmosphere) at room temperature. Evolution of hydrogen ceased.
• a solution of sodium 3,4-dimethylphenoxide was prepared by adding slowly with stirring and under nitrogen a solution of 3,4-dimethylphenol (48.86, 0.4 mole) in 250 ml of tetrahydrofuran (distilled from lithium aluminum hydride) to a suspension of 50% sodium hydride (18.2 g, 0.4 mole) previously washed with hexane and in 250 ml of tetrahydrofuran. After stirring for 30 minutes at room temperature, all evolution of hydrogen ceased and 1-(2 ⁇ -­pyridyl)-2-bromoethanol* hydrobromide (28.3 g, 0.1 mole) was added all at once in solid form. The reaction mixture was refluxed under nitrogen overnight.
• a solution of the sodium salt of 2,6-dimethylphenol was prepared by the addition of 2,6-dimethylphenol (48.86 g, 0.4 mole) in 300 ml of tetrahydrofuran to sodium hydride (19.2 g, 0.4 mole of 50% dispersion) which was previously washed with hexane and placed in 200 ml of tetrahydrofuran. The solution was stirred under nitrogen at room temperature for 0.5 hour; evolution of hydrogen ceased.
• 1-(2 ⁇ -Pyridyl)-2-bromoethanol* hydrobromide 28.3 g, 0.1 mole was added in small portions over 15 min as a solid. The mixture was refluxed under nitrogen overnight with stirring.
• a solution of the sodium salt of o -ethoxyphenol was prepared from 28.80 g (0.60 mole) of 50% sodium hydride and 82.90 g (0.60 mole) of o -ethoxyphenol in 500 ml of dimethylsulfoxide (dried over molecular sieves). The dark brown solution was stirred for one hr at room temperature (all under nitrogen). 1-(2 ⁇ -Pyridyl)-2-­bromoethanol* hydrobromide (42.45 g, 0.15 mole) was added all at once in solid form and the resulting solution was stirred under nitrogen overnight at 95°C. in an oil bath. The dimethylsulfoxide was removed by vacuum distillation to give a red oil.
• a solution of the sodium salt of p-chlorophenol in dimethylsulfoxide was prepared by the addition of p-chlorophenol (76.80 g, 0.6 mole) in 450 ml of dimethyl­sulfoxide to a sodium hydride (50%) dispersion (28.80 g, 0.6 mole) in 450 ml of dimethylsulfoxide over 45 min. The solution was then stirred for 1 hr at room temperature.
• 1-(2 ⁇ -Pyridyl)-2-bromoethanol* hydrobromide 42.15 g, 0.15 mole was added all at once and the solution was stirred overnight at 100°C.
• the dimethylsulfoxide was removed by vacuum distillation.
• a solution of the sodium salt of 2,4-dimethylphenol was prepared in 500 ml of tetrahydrofuran (distilled from lithium alunimum hydride) by the addition of 2,4-dimethylphenol (68.40 g, 0.56 mole) to sodium hydride (26.88 g of a 50% dispersion, 0.58 mole) which had been washed with hexane and dried over nitrogen. The reaction mixture was then stirred under nitrogen for 0.5 hr and hydrogen evolution ceased. 1-(2 ⁇ -Pyridyl)-2-­bromoethanol* hydrobromide (39.18 g, 0.14 mole) was added all at once as a solid. The mixture was heated under nitrogen at reflux overnight.
• a solution of the sodium salt of p-phenylphenol in tetrahydrofuran (THF) was prepared by the addition of p-phenylphenol (102.0 g, 0.6 mole) in 250 ml of THF to sodium hydride (28.80 g, 50% dispersion, 0.60 mole) which was previously washed with hexane, dried in a stream of nitrogen and placed in 250 ml of THF. The resulting solution was stirred an additional 0.5 hr at room temperature.
• 1-(2 ⁇ -Pyridyl)-2-bromoethanol* hydrobromide 42.15 g, 0.05 mole was added as a solid all at once). The resulting mixture was refluxed over­night under nitrogen.
• the sodium salt of p-hydroxyacetanilide was prepared by adding slowly with stirring under nitrogen a solution of p-hydroxyacetanilide (120.9 g, 0,8 mole) in 250 ml of dimethylsulfoxide (dried over molecular sieves) to a mixture of 50% sodium hydride (38.4 g, 0.8 mole) which was previously washed with petroleum ether and dried and subsequently placed in 250 ml of dimethylsulfoxide. The addition took place over one hour, and the reaction was then stirred for one hour at room temperature.
• a solution of the sodium salt of p-nitrophenol in dimethylsulfoxide was prepared by the addition of p-­nitrophenol (198.09 g, 1.424 mole) in 800 ml of dimethyl­sulfoxide to sodium hydride (68.35 g, 50% dispersion, 1.424 mole), which was previously washed with hexane, dried in a stream of nitrogen and placed in 250 ml of dimethylsulfoxide. The resulting solution was stirred for 0.5 hr at room temperature.
• 1-(2 ⁇ -Pyridyl)-2-­bromoethanol* hydrobromide 100 g, 0.356 mole was added as a solid over 25-30 min. The resulting mixture was stirred overnight at 95°C.
• a solution of the sodium salt of 2,6-dimethylphenol was prepared in 250 ml of dimethylsulfoxide (dried over Linde 4A molecular sieves) by the addition of 2,6-dimethyl­phenol (24.4 g, 0.2 mole) to sodium hydride (50%, 9.6 g, 0.2 mole).
• the sodium salt was stirred 1.5 hr at room temperature, all under nitrogen.
• 1-(3 ⁇ -Pyridyl)-2-­bromoethanol* hydrobromide (14.2 g, 0.05 mole) was added all at once in solid portions, and the reaction mixture was stirred overnight at 70°C.
• a solution of the sodium salt of 2,4-dimethylphenol was prepared in 500 ml of dimethylformamide by the addition of 2,4 dimethylphenol (73.2 g, 0.6 mole) to sodium hydride (19.2 g, 0.4 mole of 50%) which had been washed with hexane and dried in a nitrogen stream. The reaction mixture was stirred for 0.5 hr at room temperature.
• a solution of the sodium salt of 2,4-dimethylphenol in 500 ml of dimethylformamide was prepared from sodium hydride (50%, 19.2 g, 0.4 mole) and 2,4-dimethylphenol (73.2 g, 0.6 mole). This solution was stirred for 1 hr at room temperature. 1-(4 ⁇ -(Pyridyl)-2-bromoethanol* hydrobromide (29.2 g, 0.1 mole) was added, and the reaction mixture was stirred overnight at 85°C. The dimethylformamide was removed in vacuo . The residue was partitioned between chloroform and 10% sodium hydroxide. The chloroform layer was dried and filtered, and the solvent removed to give a dark brown oil.
• a solution of the sodium salt of phenol was prepared in dimethylformamide (500 ml) (dried over Linde 4A molecular sieves) by the addition of phenol (56.47 g, 0.6 mole) to sodium hydride (50%, 19.2 g, 0.4 mole).
• the sodium phenoxide was stirred under nitrogen for 1.5 hr at room temperature.
• 1-(3 ⁇ -Pyridyl)-2-bromoethanol* hydrobromide 29.2 g, 0.1 mole was added all at once as a solid, and the reaction was stirred overnight at 83°C.
• the dimethylformamide was removed in vacuo , and the residue was dissolved in chloroform and the solution was extracted with several portions of 10% sodium hydroxide.
• a solution of sodium 3,4-methylenedioxy-phenoxide was prepared by adding slowly with stirring and under nitrogen a solution of 3,4-methylenedioxy phenol (59.66 g, 0.432 mole) in 250 ml of tetrahydrofuran (THF) (distilled from lithium aluminum hydride) to a mixture of sodium hydride (50%) (20.74 g, 0.432 mole), (previously washed with hexane and dried) in 250 ml of THF. After stirring for 30 min at room temperature, all evolution of hydrogen ceased and 1-(2 ⁇ -pyridyl)-2-bromoethanol* hydrobromide (30.56 g, 0.108 mole) was added as a solid over a 5 min period.
• THF tetrahydrofuran
• the diacetate (9.82 g, 0.03 mole, as a viscous oil) was dissolved in 100 ml of tetrahydrofuran. To this solution was added slowly and under nitrogen with stirring, lithium aluminum hydride (3.06 g, 0.078 mole). Vigorous evolution of hydrogen occurred. The reaction mixture was stirred for 2.5 hr at room temperature and then slowly quenched with isopropanol followed by water. The reaction mixture was filtered and washed with methanol. The solvent was removed in vacuo , and the resulting oil was then partitioned between water and chloroform. The chloro­form was removed in vacuo to give 5.42 g of light brown oil.
• the maleate salt was prepared by mixing equimolar methanol solutions of the free base and maleic acid. Addition of diethyl ether caused crystallization of a solid. The solid was triturated with isopropyl ether followed by ethyl acetate to give 2.24 g (16.1%) of a brown solid, m.p. 111.5-115.0°C. Analysis: Calculated for C21H31NO7: C,61.60; H,7.63; N,3.42 Found : C,61.30; H,7.52; N,3.51
• This pyridine compound (5.18 g, 0.015 mole) was dissolved in the minimal amount of methanol and converted to the hydrochloride salt via ethereal hydrogen chloride. All solvents were removed and the volume was adjusted to 100 ml using methanol. To this methanol solution was added 1.4 g of platinum oxide and the reaction mixture was hydrogenated for 1 hr at room temperature. The methanol was removed by rotary evaporator and the residue was partitioned between dilute base and methylene chloride. Removal of methylene chloride gave 3.15 g (60% of the title compound as a red oil.
• 2-Acetylpyridine is reacted with dimethyloxosulfonium methylide in THF at 25°C. for 2 hr.
• the reaction is quenched in water, and the aqueous mixture is extracted with methylene chloride.
• the methylene chloride solution is dried over sodium sulfate and the solvent is removed in vacuo .
• the residue is reacted with sodium phenoxide in THF to give the free base of the title compound which is reacted with ethereal hydrogen chloride to give a precipitate, the title compound.
• 2-Benzoylpyridine is reacted with dimethyloxosulfonium methylide in tetrahydrofuran (THF) at 25°C. for 2 hr.
• THF tetrahydrofuran
• the reaction is quenched in water and the aqueous mixture is extracted with methylene chloride.
• the methylene chloride solution is dried over sodium sulfate and the solvent is removed in vacuo .
• the residue is reacted with sodium phenoxide in THF to give the free base of the title compound which is reacted with ethereal hydrogen chloride to give a precipitate, the title compound.
• Example 1 When in the procedure of Example 1 the following are hydrogenated in the presence of platinum oxide: ⁇ -methyl- ⁇ -phenoxymethyl-2-pyridine methanol hydrochloride, and ⁇ -phenoxymethyl- ⁇ -phenyl-3-pyridine methanol hydrochloride, there are obtained ⁇ -methyl- ⁇ -phenoxymethyl-2-piperidinemethanol hydrochloride, and ⁇ -phenoxymethyl, ⁇ -phenyl-3-piperidinemethanol hydrochloride.
• 2-(Formyl)-1-pyrrolidinecarboxylic acid phenylmethyl ester is prepared from 2-(hydroxymethyl)-1-pyrrolidine-­carboxylic acid phenyl methyl ester using pyridinium chlorochromate as described by Mori, M. in TETRAHEDRON (1985), 5465-5475, and converted to the corresponding 2-epoxide using dimethyloxosulfonium methylide obtained by mixing trimethyl sulfoxonium iodide and sodium hydride in an aprotic solvent.
• 1-Phenylmethyl-3-formylpyrrolidine is prepared from 1-phenylmethyl-3-hydroxymethyl pyrrolidine (source: method of U. S. Patent 3,318,908) by reacting it with pyridinium chlorochromate and converted to the corresponding 3-epoxide using dimethyloxosulfonium methylide obtained by mixing trimethylsulfoxonium iodide and sodium hydride in aprotic solvent.
• the epoxide is reacted with sodium phenoxide and the reaction mixture is acidified to give 1-phenyl­methyl- ⁇ -phenoxymethyl-2-pyrrolidinemethanol which is hydrogenated over palladium on carbon to give the free base of the title compound.
• the free base is converted to the hydrochloride salt as in Example 38.
• 1-Methyl-3-formylpyrrolidine is prepared from 1-methyl-­3-hydroxymethylpyrrolidine (source: method of U. S. Patent 3,318,908) by reacting it with pyridinium chlorochromate and converted to the 3-epoxide using dimethyloxosulfonium methylide obtained by mixing trimethyl sulfoxonium iodide and sodium hydride in aprotic solvent.
• the epoxide is reacted with sodium phenoxide and the mixture is acidified to give 1-(phenylmethyl)- ⁇ -(phenoxymethyl)-2-pyrrolidine­methanol which is hydrogenated over palladium on carbon to give the free base of the title compound.
• the maleate salt is prepared by mixing equimolar solutions of the free base and maleic acid in methanol.
• the N-tert-butyl formamidine derivative of homo­piperidine is prepared and reacted with butyl lithium to produce the 2-metalated product [see Chart III; J. ORG. CHEM. (1985) 50 , 1019, and J. AM. CHEM. SOC. (1984) 106 , 3270].
• This metalated homopiperidine derivative is reacted with phenoxyacetaldehyde and the reaction mixture is acidified to give 1-(tert-butyl formamidinyl)- ⁇ -­(phenoxymethyl)-homopiperidinemethanol which is isolated and heated in an aqueous methanolic solution of potassium hydroxide to give the free base of the title compound.
• the free base is converted to the hydrochloride salt by reacting with ethereal hydrogen chloride.
• 3-Carboxyhomopiperidine (Source: U. S. 4,409,146) is reacted with benzoxycarbonyl chloride to give 3-(carboxy)-­1-homopiperidinecarboxylic acid phenylmethyl ester.
• This derivative is isolated and reacted with diborane in tetrahydrofuran to give 3-(hydroxymethyl)-1-homopiperidine-­carboxylic acid phenylmethyl ester.
• This derivative is isolated and reacted with pyridinium chlorochromate to give 3-(formyl)-1-homopiperidine carboxylic acid phenylmethyl ester.
• the epoxide of this derivative is prepared by reacting with trimethyl sulfoxonium iodide and sodium hydride in an aprotic solvent. This epoxide is reacted with sodium phenoxide and the reaction mixture is acidified to give 2-(1-hydroxy-2-phenoxyethyl)-1-homopiperidine-­carboxylic acid phenylmethyl ester which is hydrogenated over palladium on carbon to give the free base of the title compound. The free base is then converted to the hydro­chloride salt as in Example 38.
• the free base of the title compound is prepared by reacting ⁇ -phenoxymethyl-2-homopiperidinemethanol with acetic anhydride and following the procedure of Example 12.
• test compounds were administered by infusion (Harvard Model 942 Infusion Pump) into a femoral vein at a rate of 1 mg/kg/min. Concentration of compound was adjusted according to the weight of the dog to allow a volume infusion of 1 ml/min. The compound was considered to be active as an antiarrhythmic agent if reversion to a sinus rhythm occurred which was maintained for at least 30 minutes.
• the animal is then taped to the table in a supine position.
• a midline incision approximately 4 cm long is made with scissors in the skin and another through the abdominal muscle wall.
• With small blunt hemostats, the skin is separated from the abdominal muscle at the midline to expose the tip of the brass tube.
• a small opening is made through the abdominal muscle at the appropriate angle with the blunt tips of the hemostats.
• a modified Week's cannula is inserted in the abdominal cavity and the other end is threaded through the brass tube until it exits at the base of the animal's neck.
• the brass tubing is removed and the 7 mm cured polyethylene tip of the cannula is aligned and positioned for insertion into the abdominal aorta.
• the positioned cannula is filled with isotonic saline.
• the abdominal viscera is gently moved to the side, exposing the aorta in the region of bifurcation.
• the aorta is isolated and 2 silk ligatures, 1 to 1.5 cm apart, are placed around it.
• the ligatures are used to briefly and gently occlude blood flow.
• the abdominal aorta is punctured craniad to the bifurcation with the tip of a 23 gauge hypodermic needle.
• the needle is removed and the tip of the cannula inserted through this opening toward the heart. Caution is taken to keep the tip vertically aligned in the aorta. Blood is allowed to flow back through the cannula to check correct insertion.
• the cannula is cleared of blood with 0.4 cc flush of isotonic saline.
• the stability of the cannula in the artery is ensured by suturing the ligature tied around the cannula to the dorsal muscle layers lying directly beside the aorta.
• the cannula is also sutured to the abdominal wall at the point of exit.
• the abdominal viscera is repositioned and the abdominal wall and skin sutured in separate layers with blanket stitch.
• the animal is given 0.2 ml Combiotic® (procaine penicillin G and dihydrostreptomycin sulfate).
• the cannula is inserted through a length of flexible metal spring, which is attached to the aluminum tubing and to a part of a swivel device that permits the animal to move with relative freedom around the cage.
• a length of flexible metal spring which is attached to the aluminum tubing and to a part of a swivel device that permits the animal to move with relative freedom around the cage.
• each rat is given a bottle of 5% dextrose containing terramycin (1 tsp. Pfizer Terramycin soluble powder/L 5% dextrose) to drink.
• the tied-off cannula is reopened and attached to the swivel device.
• One end of a saline filled length of polyethylene 50 tubing is attached to the swivel and the other to a Statham pressure transducer (Model P23ID) creating a continuous saline-arterial connection.
• Continuous tracings from the direct aortic blood pressure are recorded on a Grass polygraph (Model 7). Heart rate is determined from the blood pressure pulse.
• the electrical output of the blood pressure signal from the polygraph is fed into a Buxco Channel Cardio­vascular analyzer (Model 12).
• the blood pressure signals are averaged for a 1-min period and measurements of blood pressure and heart rate is printed on a Texas Instruments data terminal (Model 700 ASR).
• mice are continuously infused with heparin in sterile saline (2 mg/ml) at a rate of .05 to .06 ml/hr.
• Purina Mouse Chow and water are available ad libitum .
• a solution containing 5% dextrose and terramycin is given once weekly.
• Surgically prepared rats may be used more than once during a study.
• a minimum of 3 days must lapse before rats are used again.
• a rat is used only once in a dosage group.
• Test drugs were prepared as solutions using appropriate vehicles to attain solubility. Test drugs were administered to each of three rats directly through the intra-arterial catheter to achieve immediate placement of the drug into the cardiovascular circulation. An initial dose of 1 mg of the free base of test drug per kg of test subject's body weight was administered and the mean arterial blood pressure (MABP) was recorded prior to and at 5, 10, 15 and 30 minutes after test drug administration.
• MABP mean arterial blood pressure
• a second dose of the same test drug was then adminis­tered at a dose of 10 mg of free base per kg test subject's weight by the same route of administration (i.e., intra-­arterial) and measurements of the MABP was recorded prior to and at 5, 10, 15, 30, 60, 120, 180, 240, 300 and 360 minutes and 24 hr after administration of the test drug each test animal served as its own control and the absolute change from predose levels in MABP (mm Hg) induced by each test drug was determined for each time interval.
• route of administration i.e., intra-­arterial
• results were expressed as the average change in MABP (mm Hg) for three rats.
• a decrease in MABP greater than or equal to 15 mm Hg at any post-test drug adminis­tration interval is regarded as an acceptable (active) antihypertensive effect.
• Compounds such as those of Examples 5, 6, 17, 20, 25, 26, 29 and 31 were considered the more active and preferred compounds in lowering blood pressure in hypertensive rats when tested in the procedure given hereinabove.
• the invention further provides pharmaceutical compositions for administration to living mammals such as humans comprising, as active ingredients, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient.
• compositions for oral administration are preferably solids and can take the form of capsules, tablets or coated tablets containing carriers conveniently used in the pharmaceutical art.
• suitable tableting excipients include lactose, potato and maize starches, talc, gelatin and stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidine.
• the carrier or excipient can be sterile, parenterally acceptable liquid, e.g., water, or a parenterally acceptable oil, e.g., arachis oil, contained in ampules.
• parenterally acceptable liquid e.g., water
• a parenterally acceptable oil e.g., arachis oil
• Exemplary of liquid carriers for oral administration are vegetable oils and water.
• compositions for rectal administration can comprise a suppository base, e.g., cocoa butter, or a glyceride.
• unit dosages are usually from five milligrams or above and preferably 10, 25, 50, or 1000 milligrams or even higher, preferably adminis­tered three or four times per day, depending, of course, upon the emergency of the situation, the compound used, and the particular result desired. Twenty-five to 200 milligrams appears optimum per unit dose or usual broader ranges appear to be about 10 to 500 milligrams per unit dose. Daily dosages usually required should range from about 0.3 to about 20 mg/kg/day, preferably 0.3 to 10 mg/kg for the more active compounds.
• the active ingredients of the invention may be combined with other compatible pharmaceuti­cally active agents. It is only necessary that the active ingredient constitute an effective amount, i.e., such that suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician.
• compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients.
• Tablets, coated tablets, capsules, ampules and suppositories are examples of preferred dosage forms according to the invention. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed.
• the exact individual dosages, as well as daily dosages, will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian. Generally, the pharmacology on animals suggests that the oral dosage effective to correct arrhythmias will be about 3 times that of the intravenous dosage.
• unit dosages containing an amount of compound equivalent to about 1 to about 100 mg/kg of body weight are contemplated.
• a choice in a range of unit oral dosages for humans of about 10 to about 1000 mg is contemplated, preferably about 10 to 600 mg.
• Daily dosages of about 30 to 2400 mg are contemplated for humans and obviously several unit dosage forms may be administered at about the same time.
• the scope of the invention is not to be limited by these contemplations due to the uncertainty in transpositions discussed above.
• compositions within the preferred ranges given are as follows:
• compositions containing an effective amount of one or more compounds of Formula I for controlling cardiac arrhythmias and/or blood pressure are embodiments of this invention.

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• 1987
  • 1987-02-20 US US07/016,779 patent/US4835164A/en not_active Expired - Fee Related
• 1988
  • 1988-01-29 AU AU10983/88A patent/AU1098388A/en not_active Abandoned
  • 1988-02-19 KR KR1019880001753A patent/KR880009923A/ko not_active Application Discontinuation
  • 1988-02-19 JP JP63037314A patent/JPS63295552A/ja active Pending
  • 1988-02-22 EP EP88301479A patent/EP0279707A3/de not_active Withdrawn

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